The Antimicrobial/Elastase Inhibitor Elafin Regulates Lung Dendritic Cells and Adaptive Immunity

Abstract

Infections with bacteria and viruses such as adenovirus are a feature of chronic lung diseases such as chronic obstructive pulmonary diseases (COPD), and may be instrumental in the generation of disease exacerbations. We have previously shown in acute models that elafin (a lung natural chemotactic molecule for macrophages and neutrophils, with potent antimicrobial and neutrophil elastase inhibitor activity) is upregulated in infection and modulates innate immunity. Here we present data using two independent systems of elafin overexpression in vivo (recombinant adenovirus [Ad-elafin] and an elafin transgenic mouse line) to examine the function of elafin in adaptive immunity. We show that elafin increases the number (immunofluorescence) and activation status (flow cytometric measurement) of CD11c+/MHCII+ lung dendritic cells in vivo. Analysis of cytokines produced by spleen and lung cells, and of antibodies measured in serum and bronchoalveolar lavage fluid, shows that the immunity induced is biased toward a type 1 response (production of IL-12, IFN-gamma, and IgG2a). Furthermore, elafin overexpression protected mice against further challenge with Ad-LacZ, as assessed by antibody levels and neutralization titer, as well as LacZ expression in lung tissue. Thus, the pleiotropic molecule elafin has significant potential in modulating antigen-presenting cell numbers and activity, and could be beneficial in mucosal protective strategies.

Antiviral Activity of Trappin-2 and Elafin In Vitro and In Vivo against Genital Herpes

“…Nevertheless, our study shares key observations with earlier publications. Despite the differential experimental designs and suggested antiviral mechanisms of Tr, our findings of increased antiviral protection and reduced mortality are in agreement with Zaidi et al (acute model of viral myocarditis) (82) and Roghanian et al (a model of adenoviral lung challenge assessing adaptive immunity) (37). That beneficial effects of Tr/E were observed in such distinct models attests to the existence of differential mechanisms of Tr/E antiviral protection that could be attributed to the pleiotropic nature of the molecules as well as the target organ specificity.…”

“…Although this is not the first study using Etg animals against viral challenge (37,82), it is the first report pertaining to HSV-2 infection. Nevertheless, our study shares key observations with earlier publications.…”

“…Furthermore, we and others have shown that Tr/E exert immunomodulatory activity, where depending on the environment, they can either dampen inflammation or promote immunostimulatory events and prime the immune system (35)(36)(37). Tr/E are found at mucosal surfaces and in secretions, including cervicovaginal lavage fluid (CVL) (22,23,38); in tissues, like skin, placenta, and genital and gastrointestinal tracts (38)(39)(40)(41)(42)(43)(44); and in multiple cell types, such as neutrophils, macrophages, keratinocytes, and epithelial cells (12,22,45), including genital ECs (22,38).…”

Proteases and cystic fibrosis

“…Elafin, a low molecular weight inhibitor of NE that is secreted in the lung directly kills Pseudomonas aeruginosa and Staphylococcus aureus in vitro (Simpson et al, 1999). Elafin also increases the number and activation of dendritic cells after overexpression in vivo (Roghanian et al, 2006b). Aerosol treatment of human monocyte/neutrophil elastase inhibitor, a serpin that inhibits NE, cathepsin G, and proteinase-3, to mice with chronic Pseudomonas aeruginosa lung infection, inhibits lung inflammatory injury and promotes P. aeruginosa clearance (Woods et al, 2005).…”

Anti-HIV-1 Activity of Elafin Is More Potent than Its Precursor's, Trappin-2, in Genital Epithelial Cells

“…Both Tr/E and SLPI were shown to reduce activation of NF-B and AP-1 by altering IB activation (27) and proteosomal degradation (10), respectively, in response to inflammatory and bacterial stimulation. More recent studies also reported immunomodulatory properties of Tr/E, either through dampening or promoting inflammation (10,71) and priming of the immune system (43,57). We also recently found that recombinant adenovirus (Ad)-augmented Tr/E mediated increased poly(I·C)-driven antiviral protection that was associated with reduced proinflammatory factors, lower expression of RIG-I and MDA5, and attenuated NF-B activation (13).…”